tbuckley/cabot-search huggingface dataset:
Abstract 6097: Ferroptosis resistance in epithelial populations of triple negative breast cancer is mediated by laminin 332 and integrin beta4
Authors: Emmet R. Karner, Hira Lal Goel, Arthur M. Mercurio
Journal: Cancer Research (2022)

Abstract Ferroptosis is an iron dependent form of regulatory cell death caused by the accumulation of lipid peroxides that can be exploited as a therapeutic for carcinomas and possibly other cancers. However, some populations of carcinoma cells resist ferroptosis, especially those with an epithelial phenotype but the mechanisms that promote resistance are poorly understood. We discovered that ferroptosis resistance in triple-negative breast cancer cells (TNBC) with an epithelial phenotype is dependent on expression of the integrin β4 and its ligand laminin 332 (LM332). LM332 and the integrin β4 maintain an epithelial cell state by downregulation of the EMT factor ZEB1. We further demonstrate that repression of ZEB1 by integrin β4 and LM332 promotes YAP/TAZ-mediated transcription of the C2 subunit of LM332, activating a positive feedback loop. Lastly, we observed that disrupting the β4/LM332 signaling axis sensitizes epithelial TNBC cells to ferroptosis by inducing ZEB1 expression. Our findings reveal a novel role for the extracellular matrix in promoting ferroptosis resistance by sustaining an epithelial phenotype and they suggest potential therapeutic strategies for overcoming this resistance. Citation Format: Emmet R. Karner, Hira Lal Goel, Arthur M. Mercurio. Ferroptosis resistance in epithelial populations of triple negative breast cancer is mediated by laminin 332 and integrin beta4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6097.
Abstract 2: Flavokawain A targets cancer stem cells for inhibiting the growth of prostate cancer
Authors: Liankun Song, Merci Mino, Jana Yamak, Vyvyan Nguyen, Derron Lopez, Victor Pham, Ali Fazelpour, Vinh Le, Dongjun Fu, Matthew Tippin, Xiaolin Zi
Journal: Cancer Research (2022)

Abstract Prostate cancer stem cells (PCSC) are small tumor subpopulations capable of self-renewal and driving prostate cancer heterogeneity, which is critical for cancer initiation, recurrence, and development of therapeutic resistance. Thus, there’s an urgent need to explore and develop new CSC targeting agents. Flavokawain A (FKA), a novel chalcone from kava plant, can selectively inhibit the growth of pRb deficient cell lines and result in a proteasome-dependent and ubiquitination-mediated Skp2 (S-phase kinase-associated protein 2) degradation, while the potential of FKA to target PCSC is unknown. Therefore, we evaluated the effects of FKA on PCSC self-renewal both in vitro and in vivo. FKA treatment decreased both size and numbers of the tumor spheroids growing from CD44+/CD133+ tumor stem cells, which were sorted out from the prostate tumor cell line DU145 and 22RV1. Expression of the stem cell markers Nanog, Oct4, and Sox2 were all downregulated in the cancer spheroids treated with FKA. Growth of the 22RV1CD44+/CD133+ xenograft tumors was significantly inhibited in FKA diet-fed mice compared to the vehicle control diet-fed mice. Immunohistochemistry analysis revealed less positive Ki67, Nanog, and Oct4 cells in tumor tissues from the FKA dietary group than those from the control dietary group. These results demonstrated that FKA can inhibit prostate cancer stemness and suggested a potential role of FKA for preventing prostate cancer recurrence by targeting PCSC. Citation Format: Liankun Song, Merci Mino, Jana Yamak, Vyvyan Nguyen, Derron Lopez, Victor Pham, Ali Fazelpour, Vinh Le, Dongjun Fu, Matthew Tippin, Xiaolin Zi. Flavokawain A targets cancer stem cells for inhibiting the growth of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2.
Abstract 6050: JMJD6 regulates super-enhancer mediated transcriptional dependencies in group 3 medulloblastoma
Authors: Matthew Kling, Sutapa Ray, Don W. Coulter, Nagendra Chaturvedi
Journal: Cancer Research (2022)

Abstract Medulloblastoma (MB) is a heterogenous cerebellar tumor that comprises four molecular and clinically significant subgroups. MB is the most common brain malignancy in children with a five-year survival of 70%, however, Group 3 MB patients have the poorest survival due to the amplification of MYC and overexpression of key oncogenes that underly the Group 3 phenotype. Recently, epigenetic modifications bearing super-enhancer, H3K27ac, marks have been suggested to contribute to transcriptional dependencies that define Group 3 MB and represents an emerging target for therapeutic intervention. Currently, the mechanism that establishes and maintains these modifications to the DNA architecture remains unclear. In our study, we hypothesize that an epigenetic modifying protein, JMJD6, regulates the promoter-pause release associated with super-enhancer mediated oncogene addiction in Group 3 MB. This hypothesis is based on evidence in the literature showing that JMJD6 regulates the transcriptional pause release at enhancer regions. Moreover, the promoter-pause release has been shown to be critical for super-enhancer mediated transcription. In our preliminary studies, we demonstrate elevated levels of JMJD6 in Group 3 MB and survival analysis indicating JMJD6 as a predictor for poor prognosis in MB patients. Immunoprecipitation revealed that JMJD6 forms complexes with proteins involved in maintaining and regulating the promoter-pause at super-enhancers. Inducible knockdown of JMJD6 decreased MYC expression, cellular proliferation and stemness in vitro while inhibiting tumor formation and promoting survival in mice. Together, these studies identify JMJD6 as a promising therapeutic target for treating aggressive epigenetically driven Groups 3 MB tumors. Citation Format: Matthew Kling, Sutapa Ray, Don W. Coulter, Nagendra Chaturvedi. JMJD6 regulates super-enhancer mediated transcriptional dependencies in group 3 medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6050.
Abstract 2420: Exploring associations between the IL4 pathway and colorectal cancer risk in <i>in vivo</i> models and clinical records
Authors: Jacob Beckstead, Jack Petros, Kunaal Mehrotra, Barbara Fingleton
Journal: Cancer Research (2022)

Abstract We have previously demonstrated that inhibition of the IL4 pathway limits metastatic potential in colorectal cancers and have postulated that the type II IL4 receptor could serve as a potential target in risk assessment and treatment. Here we expand on these findings through in vivo mouse studies and retrospective patient analysis. To elucidate how colorectal cancers may use the IL4 pathway to grow and infiltrate surrounding tissue, we performed two in vivo studies independently targeting IL4ra in myeloid and intestinal epithelial tissues. Mice with a deleted allele of IL4ra and a floxed allele of IL4ra were crossed with either a line expressing a myeloid-specific Cre (LysM Cre) or an intestinal epithelial-specific Cre (Villin Cre). Our results indicate that myeloid-expressed IL4ra facilitates tumorigenesis but is not a significant contributor to later growth. In contrast, epithelial IL4ra significantly contributes to tumor number and size, but had little effect on the observed number of aberrant crypt foci, an early indicator of colon cancer. We hypothesized that effects of atypical IL4 activity could also be observed in the medical record. Atopic diseases such as asthma and eczema are characterized by an overabundance of IgE, a protein regulated by the IL4 pathway. Using Vanderbilt University Medical Center’s SD Discover program, we obtained de-identified records for patients diagnosed with at least stage II colorectal carcinoma between 2005 and 2015. We then stratified patients by metastatic progression. Patients who were diagnosed with asthma prior to age sixty were significantly less likely to develop an advanced form of colorectal cancer and at reduced risk of metastatic disease or recurrence. This may be a result of medication prescribed for atopic disease such as inhalers and corticosteroids and we are performing further analyses to test these hypotheses. Citation Format: Jacob Beckstead, Jack Petros, Kunaal Mehrotra, Barbara Fingleton. Exploring associations between the IL4 pathway and colorectal cancer risk in in vivo models and clinical records [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2420.
Abstract 937: Novel role of deubiquitylase USP13 in lineage plasticity and drug resistance of non-small cell lung cancer
Authors: Juntae Kwon, Cecil Han
Journal: Cancer Research (2022)

Abstract Lineage plasticity, the ability of cells to transition from one defined cell type to another, has been proposed as a source of intertumoral heterogeneity and therapeutic resistance.However, molecular drivers and underlying mechanisms of lineage plasticity remain largely unknown. Here, we found a novel role of deubiquitylase USP13 in lineage transition of lung adenocarcinoma (ADC) to squamous cell carcinoma (SCC) using mouse model: Usp13-overexpressing (Usp13OE) ADC loses its characteristics while gaining SCC features are enhanced. Transcriptomic analysis showed that Usp13OE lung cancers were heterogeneous and epithelial-mesenchymal transition (EMT), hypoxia, and PI3K-Akt-mTOR signaling pathway were enriched. Furthermore, development disease pathways including neurological and gastrointestinal diseases were overrepresented in Usp13OE tumors. Notably, Usp13OE primary tumor cell lines showed higher drug resistance against first-line therapy. Collectively, our findings demonstrate the novel role of USP13 in lineage transition of lung cancer and suggest that targeting USP13 is a promising strategy for the further treatment of lung cancer patients. Citation Format: Juntae Kwon, Cecil Han. Novel role of deubiquitylase USP13 in lineage plasticity and drug resistance of non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 937.
Incidence of typhoid and paratyphoid fever in Bangladesh, Nepal, and Pakistan: results of the Surveillance for Enteric Fever in Asia Project
Authors: Denise O Garrett, Ashley T Longley, Kristen Aiemjoy, Mohammad T Yousafzai, Caitlin Hemlock, Alexander T Yu, Krista Vaidya, Dipesh Tamrakar, Shampa Saha, Isaac I Bogoch, Kashmira Date, Senjuti Saha, Mohammad Shahidul Islam, K M Ishtiaque Sayeed, Caryn Bern, Sadia Shakoor, Irum F Dehraj, Junaid Mehmood, Mohammad S I Sajib, Maksuda Islam, Rozina S Thobani, Aneeta Hotwani, Najeeb Rahman, Seema Irfan, Shiva R Naga, Ashraf M Memon, Sailesh Pradhan, Khalid Iqbal, Rajeev Shrestha, Hafizur Rahman, Md Mahmudul Hasan, Saqib H Qazi, Abdul M Kazi, Nasir S Saddal, Raza Jamal, Mohammed J Hunzai, Tanvir Hossain, Florian Marks, Alice S Carter, Jessica C Seidman, Farah N Qamar, Samir K Saha, Jason R Andrews, Stephen P Luby
Journal: The Lancet Global Health (2022)

Precise enteric fever disease burden data are needed to inform prevention and control measures, including the use of newly available typhoid vaccines. We established the Surveillance for Enteric Fever in Asia Project (SEAP) to inform these strategies.
Vision Impairment Has Implications for Aging and Health Outcomes, Beyond Ophthalmology
Authors: Varshini Varadaraj, Joshua R. Ehrlich, Bonnielin K. Swenor
Journal: JAMA Network Open (2022)

US Preventive Services Task Force; Carol M. Mangione, MD, MSPH; Michael J. Barry, MD; Wanda K. Nicholson, MD, MPH, MBA; Michael Cabana, MD, MA, MPH; David Chelmow, MD; Tumaini Rucker Coker, MD, MBA; Esa M. Davis, MD, MPH; Katrina E. Donahue, MD, MPH; John W. Epling Jr, MD, MSEd; Carlos Roberto Jaén, MD, PhD, MS; Alex H. Krist, MD, MPH; Martha Kubik, PhD, RN; Li Li, MD, PhD, MPH; Gbenga Ogedegbe, MD, MPH; Lori Pbert, PhD; John M. Ruiz, PhD; Melissa A. Simon, MD, MPH; James Stevermer, MD, MSPH; John B. Wong, MD
Abstract 396: Therapeutic targeting of eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) in enzalutamide resistant (ENZR) prostate cancer
Authors: Praveen K. Jaiswal, Sweaty Koul, Saikolappan Sankaralingam, Hari K. Koul
Journal: Cancer Research (2022)

Abstract Objective: Deregulation of the translation initiation machinery is one of the critical steps for oncogenic mRNA translation in tumor cells. Eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) is a crucial scaffold of translation initiation complex (EIF4F). Our recent studies suggest a role for EIF4G1 in multiple tumor types including prostate cancer progression. In the present study, we tested the unknown function of EIF4G1 in Enzalutamide resistant prostate cancer cells. Methods: We used enzalutamide resistant C4-2B (C4-2BENZR) and parental C4-2B cells for the current study. For the functional studies, we used shRNA targeting the EIF4G1 and pharmacological EIF4G-EIF4E complex inhibitor (4EGI-1). The functional assays such as clonogenic, cell proliferation, cell viability, trans-well migration/invasion, and prostasphere formation were performed. To further expand in vitro findings we employed, in-vivo tumor xenograft model derived from enzalutamide resistance C4-2B cells. Results: We found a higher level of EIF4G1 protein in ENZ resistance (C4-2B ENZR) cell lines as compared to parental C4-2B cell lines. Furthermore, knockdown of EIF4G1 by shRNA or treatment with 4EGI-1 inhibitor impaired the clonogenic potential, prostasphere formation, cell viability/proliferation, and cell migration/invasion in C4-2B ENZR cell line, suggesting a critical role of EIF4G1 in modulating enzalutamide resistance in CRPC cells. C4-2BENZR subcutaneous tumor xenograft treated with&amp;#x2028;combination of 4EGI-1 and ENZ were significantly reduced the tumor volume. Moreover 4EGI-1 sensitized ENZ Resistance C4-2B cells to Enzalutamide treatment in tumor xenograft model. Conclusions: Overall, the findings suggest that EIF4G1 could serve as a novel therapeutic target in overcoming therapeutic resistance to current treatments in PCa. Citation Format: Praveen K. Jaiswal, Sweaty Koul, Saikolappan Sankaralingam, Hari K. Koul. Therapeutic targeting of eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) in enzalutamide resistant (ENZR) prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 396.
Abstract 2521: Impact of peritoneal lavage on omentum immune cell dynamics and metastasis
Authors: Hironari Akasaka, Honami Naora
Journal: Cancer Research (2022)

Abstract Peritoneal lavage is a routine procedure in which normal saline solution is administered into the abdominal cavity and the washings are cytologically examined for cancer cells. Peritoneal lavage often strips protective mesothelial linings and can promote formation of peritoneal adhesions. However, the impact of peritoneal lavage on the omentum, which is also exposed to this procedure, is unclear. The omentum is a fatty tissue that suspends from the stomach and contains highly vascularized immune cell structures called milky spots. Because circulating ovarian and gastric cancer cells have strong predilection for implanting in milky spots, it is important to understand the impact of peritoneal lavage on the omentum, as not all patients with these cancers undergo omentectomy. In this study, we administered clinically relevant amounts of normal saline solution to immunecompetent mice to mimic peritoneal lavage, and evaluated the absorption of saline solution and the gross architecture and immune cell composition of the omentum and other peritoneal fat tissues. As compared to other peritoneal fat tissues, the omentum showed the highest capability to absorb saline solution. Following administration of saline, a dramatic expansion in milky spots and increased vessel density were observed in the omentum. Immunophenotyping and functional studies revealed that these cellular changes were due in part to the expansion of a sub-population of peritoneal macrophages. Furthermore, studies using mouse allograft models of ovarian cancer revealed that saline administration stimulated the implantation of circulating cancer cells on to the omentum. Collectively, these findings raise the possibility that peritoneal lavage ‘primes’ the omentum to be conducive for colonization by occult cancer cells that circulate in the peritoneal fluid. Citation Format: Hironari Akasaka, Honami Naora. Impact of peritoneal lavage on omentum immune cell dynamics and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2521.
Abstract 168: DDR2 regulates angiogenesis via HSP-90 modulation in ovarian cancer
Authors: Favour A. Akinjiyan, Ritu M. Dave, Gregory Longmore, Katherine C. Fuh
Journal: Cancer Research (2022)

Abstract Ovarian cancer is often diagnosed in later stages and patients have low five-year survival. There is a need to develop better therapies for this patient population. Solid tumors like ovarian cancer respond to hypoxia by inducing the sprouting of new blood cells. This process is called angiogenesis. Angiogenesis leads to formation of disordered and immature vessels that precludes efficient drug delivery. Prior work has shown that overexpressing DDR2 in endothelial cells leads to increased angiogenic activity, measured by tube formation and sprouting. We show that DDR2 expression in ovarian cancer tumor cells modulates angiogenic activity in endothelial cells. Human umbilical vein endothelial cells (HUVECs) cultured in conditioned media from DDR2-expressing tumor cells (ES2 shSCRM) have 20% increase in tube length and 18% increase in sprout network area than HUVECs cultured in conditioned media from DDR2-depleted tumor cells (ES2 shDDR2) (P=0.032). This difference in HUVEC angiogenesis is mediated by vascular endothelial growth factor (VEGF). We observed a 16% decrease in VEGF levels in conditioned media from ES2 shDDR2 cells compared to media from ES2 shSCRM cells (P​​&amp;lt;0.0001). DDR2 WT mice bearing ID8 Trp53-/- BRCA2-/- tumors have 53% more CD31+ microvessels than DDR2 KO mice (P​​&amp;lt;0.0001). We also identified that DDR2’s role in angiogenesis is mediated by the Hsp70/90 chaperone machinery. In summary, we have identified that DDR2 regulates angiogenesis in ovarian cancer. Citation Format: Favour A. Akinjiyan, Ritu M. Dave, Gregory Longmore, Katherine C. Fuh. DDR2 regulates angiogenesis via HSP-90 modulation in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 168.
Abstract 4070: Caveolin-1 functions as a potential predictive biomarker for JNTX-101, an albumin encapsulated gemcitabine prodrug
Authors: Tiantian Cui, Sergio Corrales-Guerrero, Dan Maneval, Curtis Monnig, Patrick Kearney, Sam Ellis, Terence M. Williams
Journal: Cancer Research (2022)

Abstract Purpose: Human serum albumin (HSA) is an attractive candidate as a carrier in developing novel albumin-bound nanoparticle therapeutic drugs. Gemcitabine has been used in the treatment of solid tumors, including non-small cell lung, pancreatic, bladder, and breast cancers. Our previous work in pancreatic and lung cancer models demonstrates that caveolin-1 (Cav-1) enhances uptake of albumin and albumin-conjugated drugs. The aim of this study is to investigate whether the presence of Cav-1 expression alters therapeutic efficacy of JNTX-101, a novel albumin encapsulated gemcitabine prodrug. Experimental design: We first determined the treatment efficacy of JNTX-101 in a panel of 4 pancreatic/lung cancer cell lines (MIAPaCa-2, PANC-1, H23, and HCC15) by alamarBlue cell viability assay. We further established 4 pairs of Cav-1 isogenic cells stably expressing shRNA targeting Cav-1 (shCav-1) or scrambled control shRNA (shCtrl). We investigated whether the absence of Cav-1 expression alters sensitivity of JNTX-101 using alamarBlue cytotoxicity assay and western blotting in both high and low serum conditions. In addition, we tested whether JNTX-101 treatment can alter expression and cellular distribution of Cav-1 as well as other caveolae resident proteins, such as Cav-2 and Cavin-1. Results: Differences in Cav-1 expression resulted in different uptake of albumin prodrug conjugate and Cav-1 depletion attenuated sensitivity of the cells to JNTX-101. Decreased Cav-1 expression markedly reduced JNTX-101-induced apoptosis in a panel of cells in both high and low serum conditions, but particularly in low serum conditions. In addition, our data showed both serum starvation and JNTX-101 independently increased Cav-1 expression in a time-dependent manner (24hrs, 48hrs, 72hrs) similar to gemcitabine, with peak level at 48 hrs post treatment, while other caveolae resident proteins were minimally affected. Conclusions: Our preliminary results suggest that JNTX-101 effectively inhibits cell viability in pancreatic/lung cancer cells and Cav-1 expression dictates sensitivity to JNTX-101, at least partially through reduced apoptotic cell death. These data indicate that Cav-1 may be a potential predictive biomarker of JNTX-101 sensitivity, especially in nutrient deprived conditions. Further study will be performed to explore the impact of Cav-1 expression on JNTX-101 sensitivity in mouse models of pancreatic/lung cancer. Citation Format: Tiantian Cui, Sergio Corrales-Guerrero, Dan Maneval, Curtis Monnig, Patrick Kearney, Sam Ellis, Terence M. Williams. Caveolin-1 functions as a potential predictive biomarker for JNTX-101, an albumin encapsulated gemcitabine prodrug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4070.